Quaternary ammonium salts of dialkylaminoalkyl esters of thiaxanthene-10-carboxylic acid



United States Patent QUATERNARY AMMONIUM SALTS 0F DIALKYL- AMINOALKYLESTERS 0F THIAXANTHENE-lfl- CARBOXYLIC ACID John W. Cusic, Skokie, andRichard A. Robinson, Morton Grove, Ill., assignors, by mesneassignments, to G. D. Searle & Co., Skokie, 111., a corporation ofDelaware No Drawing. Application July 2, 1954, Serial No. 441,177

2 Claims. (Cl. 260-328) This invention relates to quaternary ammoniumsalts of dialkylaminoalkyl esters of thiaxanthene-lO-carboxylic acid andto the production thereof. In particular this invention relates toquaternary ammonium salts of the following general structural formulawherein Alk is a lower alkylene radical, X is one stoichiometricequivalent of an anion, and R, R and R" are lower alkyl radicals.

This application is a continuation-impart of our copending applicationSerial No. 286,612, filed May 7, 1952, now abandoned.

In the compounds of the type disclosed above Alk represents a loweralkylene radical containing at least two carbon atoms and not more thanfive carbon atoms. It is a bivalent, saturated, aliphatic radical suchas the ethylene, trimethylene, propylene, or butylene radical. Xrepresents a monovalent anion such as chloride, bromide, iodide, methylsulfate, ethyl sulfate, benzene-sub fonate, nitrate, acetate and thelike, as well as one stoichiometric equivalent of a monovalent anionsuch as sulfate, phosphate, citrate, succinate, tartrate, and the like.Such anions are non-toxic in therapeutic dosage. R, R, and R" representsuch lower alkyl radicals as methyl, ethyl, propyl, isopropyl, butyl,and secondarybutyl.

The compounds of this invention are prepared by reacting adialkylaminoalkyl ester of the formula with an alkyl ester of a strongorganic or inorganic acid of the formula R"--Z wherein all symbols havethe meanings given hereinabove and Z represents halogene, alkyl sulfate,or arylsulfonate radicals. These reactions are preferably carried out atelevated temperatures in the range of 50l50 centigrade in inert solventssuch as acetone, methyl ethyl ketone, lower alcohols, chloroform, andnitromethane. However, lower temperatures from 0 to 50 C. are alsosatisfactory. Generally these reactions are preferably carried out in aclosed system if a lower alkyl halide is used as one of the reagents. Inmost instances the crystalline quaternary salt precipitates from thechilled reaction mixture and may be isolated by filtration and dried. Incertain instances, it is necessary to precipitate the salt by theaddition of a solvent, such as ether or a low boiling aliphatic oraromatic hydrocarbon in order to lower the solubility of the salt in theselected solvent. The anion Z, when it represents halogen, alkyl sulfateor arylsulfonate radicals, may be replaced by one equivalent of anotheranion of the type disclosed above, by reaction with a heavy metal salt,such as silver acetate, silver citrate, silver tartrate, silverbenzoate, lead acetate, lead benzoate, silver malate, silver nitrate andthe like.

The compounds of this invention are generally soluble in water oraqueous solutions of acohols and other watersoluble organic solvents.They exhibit surface-active properties and certain of them are useful asantiseptics and dispersing agents. They are also of value as medicinalagents, having sympatholytic properties. The compounds of this inventionare anticholinergic drugs, and have the property of blocking orinhibiting the transmission of nervous impulses across ganglia.

Our invention is disclosed in detail by the following examples which arerepresentative of methods of preparing the compounds within the scope ofthis invention, but which are not to be construed as limiting theinvention in spirit or scope. Relative amounts of materials are given inparts by weight, temperatures are given in degrees centigrade C.) andpressures in millimeters (mm.) of mercury. The organic acids in thisapplication are named and numbered according to The Ring Index, byPatterson and Capell, Reinhold Publishing Co., New York, N. Y., 1940.

Example 1 A solution of 150 parts of tl-riaxanthene-lO-carboxylic acidand parts of 'y-dimethylaminopropyl chloride in 1200 parts of absoluteisopropyl alcohol is refluxed for two hours and then allowed to standovernight. The reaction mixture is evaporated to dryness and the residueis dissolved in 1000 parts of water, washed with ether, and madealkaline with saturated sodium carbonate solution. The alkaline solutionis extracted with ether and the ether extract is Washed with water,dried with sodium sulfate, and filtered. The filtrate is evaporated todryness and the residue is dissolved in 800 parts of anhydrous methylethyl ketone. Gaseous methyl chloride is bubbled through the resultingsolution until 40 parts are taken up. The solution is allowed to standuntil the crystalline precipitate of 'y-dimethylaminopropylthiaxanthene-lO-carboxylate methochloride precipitates out. Thismaterial is collected on a filter, washed well with methyl ethyl ketoneand dried. It has the formula Example 2 50 parts of ,B-diethylaminoethylthiaxanthene-lO-carboxylate hydrochloride are dissolved in the minimumamount of water, treated with an excess of concentrated sodium carbonatesolution and the resulting base is extracted with ether. The etherextract is washed with water, dried with anhydrous sodium sulfate,filtered and evaporated. 34 parts of the residue of fi-diethylaminoethylthiaxanthene-10-carboxylate thus obtained are dissolved in parts ofmethyl ethyl ketone. 14.5 parts of methyl bromide gas are passed intothe chilled solution. There is a slight evolution of heat, indicatingreaction. On standing at room temperature crystals form rapidly. Thecrystalline precipitate of /3-diethyl-aminoethylthiaxanthene-lO-carboxylate methobromide is collected, washed with etherand dried. The salt is readily 3 soluble in Water and alcohol. Afterrecrystallization from mixtures of isopropanol and butanone, andisopropanel and ethanol, it melts at 208-209" C.

Example 3 A solution of 15 parts of fl-di ethylaminoethyl xanthene-9-carboxylateand 10 parts of ethylene bromohydrin in 60 parts ofbutanone are refluxed'fo-r 15 hours. On cooling a heavy precipitate ofB-(p-hydroxyethylethylamino)- ethyl xanth'ene-9-carboxylate ethobromideforms. This is recrystallized from a mixture" of isopropanol andbutanone, and melts at about 149 C. It hasthe formula 325- parts ofp-diethylarninoethyl xanthene-9 carboxylate and 171 parts of benzylbromide are dissolved in l250ipar'ts of butanone and-the resultingsolution is refluxed-forYan. hour. Crystals ofthe quaternary salt beginto separate during the reaction and on chillingthe mixture? becomes aslurry. The; salt iscollected on a filter, washed with cold butanone andwith ether,- and dried in a'vacuum. desiccator. A sample offidiethylaminoethyl xanthene-9-carb'oxylate benzyl broinide on analysis.showed15.9l% bromine; the calculated value is 16.08%. i i

Example} A. parts ofxanthone in 135 parts of thiophene-free, dryfhen zne and 1120'parts: of dry ether containing: in suspensiouo parts ofpowdered sodium are agitated vigor; ously for'SO'hours and. then pouredonto an excess of solid carbondioxidef After the carbon dioxide is gone,the' lresulting solution is extracted with dilute sodium carbonat'esolution; The resulting solution is warmed lwith decolorieing charcoal,cooled, filtered, and acidified. The 9-hydroxyxanthen e-9rcarboxylicacid is collected on a filter and dried. -It meltsat 129-131 C. i A

B. 6 parts of 9-hydroxyxanthene-9carboxylic acid and 6 parts 'ofB-diethylarnirioethyl chloride inBiOpparts of ISQQPIZQPQBQII are heatedto reflux for 2 hours and then left at 'room temperature for 15 hours.The solvent is re Q edl ju er vacuum arms: (2. The residue "ofpdiethylarn oethyl 9-hy'droxyxahthene-9rcarboxylate hydrochloridels'difislllvedii water; The solution is madealkaline andextracted withether. The etherextraetisdried and evaporated. The residue offi-diethylatninoethyli hydroxyxanthene-9-carboxylate is dissolved indiyether, treated witlydecolorizing charcoal, filte ged and treated with anexcess of hydrogen chloride in absolute alcohol. The oily precipitateofth e' hydrochloride is removed and dried in vacuum. It is taken up inhot absolute ethanol and allowed to evaporate slowly in a desiccator.There is thus obtained an amorphousresidue of fl-diethylaminoethyl9-hydroxyxanthene-9 carboxylate hydrochloride. A sampleon' analysisshowed 9.80% chlorine; the calculated value is 9.40%.

C. 3' parts of p-diethylaminoethyl 9-hydroxyxanthene- 9-carboxylate and2 parts of methyl bromide in 15 parts of methyl ethyl ketone are heatedin a closed vessel for l5;h 0urs'at 90-100 C. The oily precipitate ofthe quaternarysalt is separated and dried invacuum. It is trituratedwith dry ether, washed and dried in vacuum. Itlforms anamorphou powderwithout a definite melting point. A sample of the methobromide offi-diethyle aminoethyl 9- hydroxyxanthene-9-carboxylate showed onanalysis. 18.68% ofv bromine; the calculated value is 85. 0

Exqmpleo A solution of 270 parts of 9-methylxanthene in 650 parts of drybenzene is added to a solution of butyllithium prepared from 411 partsof n-butyl bromide and 42 parts of lithium in 3000 parts of dry ether.The solution is refluxed for three hours, then poured onto an excess ofsolid carbon dioxide. The mixture is extracted with water and theextract is acidified. The precipitate of 9-methylxanthene-9-carboxylicacid is collected on a filter, washed thoroughly with water and dried.

A solution of 46 parts of 9-methylxanthene-9-carboxylic acid and 30parts of B-diethylaminoethyl chloride in parts of isopropanol isrefluxed for 4 hours. The solution is chilled and diluted with dryether. On standing at low temperature a crystalline precipitate offl-diethylaminoethyl 9-methylxanthene-9-carboxylate hydrochloride forms.This is collected on a filter, washed with ether and dried. It isdissolved in a minimum of warm water and treated with an excess ofconcentrated sodium carbonate solution. The free base,B-diethylaminoethyl 9-methylxanthene-9-carboxylate, is extracted withether and the extract is washed with water, dried and evap? orated.

35 parts of fi-diethylaminoethyl 9-methylxanthene-9- carboxylate aredissolved in parts of chloroform and gaseous methyl bromide is passedinto the chilled solution until 15 parts are absorbed. The solution isthen heated in a closed vessel at 70 C. for 5 hours. The reactionmixture is chilled and diluted with dry ether. The precipitate ofB-diethylaminoethyl 9-methylxanthene- 9-carboxylate methobromide isremoved and washed with ether. A sample on analysis showed 18.2%bromine; the calculated value is 18.4%.

Example 7 An agitated solution of parts of di-p-bromophenyl ether and250 parts of oxalyl chloride inv 950 parts, of carbon disulfide ischilled in ice and treated with. 100 parts of anhydrous aluminumchloride over a periodof /2 hour, the temperature being maintained below5 C. The mixture is stirred for 1 /2 hours at ice temperature, thentreated with 80 parts of anhydrous aluminum chloride and agitated for 4hourslonger at low temperature. The reaction mixture is left atroomvtemperature for. 16 hours. It is decomposed with ice and dilutemuriatic acid.- The organic layer is separated, washed with water anddried. On evaporation there is obtained a residue of.t2,7-dibromoxanthone.

A; mixture of 9 parts of red phosphorus and 6 parts of-iodine in 100parts of propionic acid is agitated and a solution of 50 parts of2,7-dibromoxanthone in 100 parts of propionic acid is added. The mixtureis warmed and agitatedand then 8 parts of water are added slowly. Themixture is agitated and refluxed for 46 hours, then poured into 750parts of ice water. The precipitate is removed, washed with water, driedand dissolved in chlorofiorm. The chloroform solution is filtered andevaporated, leaving a residue of 2,7'-dibromoxanthene.

In 100 parts of diethylene glycol diethyl ether are dissolved 1( ).5 part s of naphthalene and 4.6 parts of 50% sodium-naphthalene powder. Thesolution is chilled to 35 C. and placed in av nitrogen atmosphere. Tothe stirred solution 17 parts of 2,7-dibromoxanthene are addedfiin=portions, the temperature being. maintainediat 30C. r0 -35 C. Themixtureis stirred and-allowed towarm to. room temperature. It is thenpoured. on an excess-of solid carbon dioxide-in 150. parts ofrtoluene.Afterthe carbon dioxide is consumed water is added and the-aqueous-layeris separated and acidified. A precipitate-of 2,7 dibromoxanthene 9carboxylic acidforms. This is collected. on a. filter, washed with waterand' dried.

A'solution-of- 12.3 parts of 2,7-dibromoxanthene-9- carboxylic acid and4.6-parts of fi-diethylaminoethyl chloride ii -65 parts of isopropanolis refluxedS hours. The solventis removed. by evaporation and theresidue, of p-diethylamino'ethyl 2,7-dibromoxanthene 9-carboxylatehydrochloride is dissolvedin water. The solution is made alkaline withconcentrated sodium hydroxide solution and the basic ester is extractedwith ether. The ether solution is washed with water, dried andevaporated. There is thus obtained ,8 diethylaminoethyl 2,7dibromoxanthene-9-carboxylate as a light colored viscous oil. It istaken up in 100 parts of butanone and 20 parts of methyl bromide areadded. The solution is heated in a closed vessel at 65 C. for two days.The solvent is then evaporated to about /3 volume and dry ether isadded. A precipitate of B-diethylaminoethyl 2,7-dibromoxanthene-9-carboxylate methobromide is formed. This is removed, washed with etherand dried. A sample on analysis showed 41.16% bromine; the calculatedvalue is 41.47%. The salt has the formula CH (12H; 6 011- OO-OHsCHr-NExample 8 A solution of 115 parts of di-p-methoxyphenyl ether and 250parts of oxalyl chloride in 1000 parts of carbon disulfide is chilled to0 C. Then 100 parts of anhydrous aluminum chloride are added slowly withgood agitation, the temperature being maintained below C. The reactionmixture is agitated for 2 hours at 0-5 C., then 50 parts of anhydrousaluminum chloride are added and agitation is continued at lowtemperature for 3 hours. The mixture is left at room temperature andthen decomposed with ice and muriatic acid. The carbon disulfide layeris washed with water and evaporated. The residue of2,7-dimethoxyxanthone is digested with hot 10% sodium carbonatesolution, filtered, washed with water and dried.

A solution of 40 parts of 2,7-dimethoxyxanthone in 800 parts of ethanolis treated with 80 parts metallic sodium at such a rate that gentlerefluxing is maintained. The solution is refluxed for 2 hours longer andpoured into 4000 parts of ice and water. The precipitate of2,7-dimethoxyxanthene is removed and dried.

Sodium-naphthalene solution in diethylene glycol diethyl ether isproduced as in Example 7 from 9 parts of 50% sodium-naphthalene powderand 21 parts of naphthalene in 200 parts of diethylene glycol diethylether. The solution is placed in a nitrogen atmosphere and chilled to 30C. 12 parts of 2,7-dimethoxyxanthene are added in portions with goodagitation, the temperature being kept below 25 C. The reaction mixtureis allowed to come to room temperature and is then poured on an excessof solid carbon dioxide in 140 parts of toluene. When the carbon dioxideis gone, water is added and the organic layer is separated. The aqueouslayer is acidified and the precipitate of2,7-dimethoxyxanthene-9-carb0xylic acid is collected on a filter, washedwith water and dried.

28 parts of 2,7-dimethoxyanthene-9-carboxylic acid and 15 parts ofB-diethylaminoethyl chloride are dissolved in 200 parts of isopropanoland refluxed for 3 hours. The solution is evaporated and the residue offl-diethylaminoethyl 2,7-dimethoxyxanthene-9-carboxylate hydrochlorideis dissolved in water and treated with an excess of concentratedpotassium carbonate solution. The basic ester is extracted with etherand the ether extract is dried and evaporated. 10 parts offl-diethylaminoethyl 2,7-dimethoxyxanthene-9 carboxylate are dissolvedin 40 parts of butanone and treated with parts of methyl bromide. Theresulting solution is heated in a closed vessel at 6070 C. for 16 hours.The chilled solution is diluted with dry ether and the precipitate ofp-diethylaminoethyl 2,7 dimethoxyxantheue-9-carboxylcrystallized fromisopropanol.

ate methobromide is collected on a filter, washed with ether and dried.A sample on analysis showed 16.38%

bromine; the calculated value is 16.64%. This'salt has the formula OOHaH-OOO-GH OHz-N OOH:

Example 9 260 parts of xanthene-9-carboxylic acid chloride and 141 partsof fi-diallylaminoethanol are dissolved in 1600 parts of butanone. Aslight exothermic reaction takes place upon mixing. The solution is thenrefluxed for 5 hours and evaporated to remove most of the solvent. Onstanding at low temperature a heavy precipitate of ,S-diallylaminoethylxanthene-9-carboxylate hydrochloride forms. This salt is collected on afilter, washed with cold butanone and dried. It melts at 147-148 C. Thissalt is dissolved in water and treated with a concentrated solution ofpotassium carbonate. The free base is extracted with ether and the ethersolution is dried and evaporated. 22 parts of fi-diallylaminoethylxanthene-9- carboxylate thus obtained are dissolved in parts ofchloroform and treated with 26 parts of methyl bromide. The resultingsolution is heated at C. in a closed vessel for 17 hours. The reactionmixture is chilled and diluted with anhydrous ether. An oily precipitateforms that soon solidifies. This precipitate is removed andrefl-Diallylaminoethyl xanthene-9-carboxylate methobromide thus obtainedmelts at l34-135 C.

Example 10 15 parts of B-diethylaminoethyl thiaxanthene-lO-carboxylateand 20 parts of crotyl bromide in parts of butanone are reacted at 50 C.for 15 hours. The solvent is then removed by evaporation and the residueof B- crotylethylaminoethyl thiaxanthene-IO-carboxylate ethobromide istriturated in cold acetone. There is thus obtained in solid form thequaternary salt of the formula A sample on analysis showed 16.59%bromine; the calculated value is 16.78%.

Example 11 25 parts of B-dimethylaminobutyl xanthene-9-carboxylate and15 parts of phenethyl bromide in 80 parts of butanone are refluxed for17 hours. The solvent is then removed under vacuum and the residue ofthe quaternary ammonium salt is triturated with dry ether. A sample ofthe salt on analysis showed 15.62% bromine; the calculated value is15.66. The salt has the formula Example 12 220 parts of2,7-dimethylxanthone are dissolved in 4000 parts of hot alcohol and 400parts of metallic sodium are added to the refluxing solution over aperiod 7 of about} hours. The solution is then poured into 20,000 parts.of ice water and the precipitate, of 2,7-dimethylxanthene is collectedon a filter, washed with water, and dried. After recrystallization froma mixture of dioxane and water, this product melts at 164-166" C.

A solution ofsodium-naphthalene in diethylene glycol diethyl ether isprepared as in Example 7 from 46 parts of 50% sodium-naphthalene powder,105' parts of naphthalene, and 1000 parts of diethylene glycol diethylether. The solution is chilled under an atmosphere of nitrogen to 25 C.and 105 parts of 2,7-dimethylxanthene are added with good agitation. Thereaction mixture is allowed to come to room temperature, and it is thenpoured on an excess of solid carbon; dioxide in 750 parts of toluene.After the carbon dioxide, is consumed, Water is added, and the aqueouslayer is separated'and acidified. The. precipitate of2,7dimetltyliranthene-9 carboxylic acid is collected on a filter, washedwith water, and dried. This acid melts at 226-230 C. with decomposition.A, solution of 82 parts of 2,7-dimethylxauthene 9- carboxylic acid and46 parts of .p-dicthylarninoethyl chloride in 500 parts of isopropanolis refluxed for 3 hours. The solvent is then removed'under vacuum andthe residue of fi-diethylaminoethyl 2,7-dimethylxanthene- 9 -carboxylatehydrochloride is taken up in water containing 21 small amount of dilutehydrochloric acid. The aqueous solution is washed twice with ether, thenmade alkaline with caustic soda solution, and extracted twice with etherto remove the basic ester thus liberated. The ether extract is washedwith water, dried and, evaporated, leaving a residue ofB-diethylaminoethyl 2,7-dimethylxanthene-9-carboxylate as a lightcolored viscous oil. This basic ester, when dissolved in dry ether and;treated with anequivalent of hydrogen chloride in absolute isopropanol,forms a crystalline hydrochloride which melts at l42l43 C., afterrecrystallization from a mixture of ethyl acetate and petroleum ether.

50 parts of [i-diethylaminoethyl 2,7-dimethylxanthene- 9-.carboxylateare dissolved in 1000 parts of butanone. The solution is chilled andtreated with gaseous methyl bromide until about 100 parts are taken up.This solu- We claim:

1. A quarternary ammonium salt of a dialkylaminoalkyl ester ofthiaxanthene-IO-carboxylic acid, having the formula wherein All; isalower alkylene radical, R, R and R" are lower alkyl radicals and X is anon-toxic anion.

' 2. B-Diethylaminoethyl thiaxanthene 10 carboxylate methobromide,having the formula References Cited in the file of this patent UNI-TEDSTATES PATENTS 2,659,732 Cusic et al. Nov. 17, 1953

1. A QUARTERNARY AMMONIUM SALT OF A DIALKYLAMINOALKYL ESTER OFTHIAXANTHENE-10-CARBOXYLIC ACID, HAVING THE FORMULA